Low-dose Buprenorphine Initiation for Opioid Use Disorder

This pilot study is designed to establish the feasibility of a future, full-powered clinical trial. The primary question this study seeks to answer is whether primary care patients with opioid use disorder are willing to enroll in a clinical trial of low-dose inductions. The study will aim to enroll 25% of subjects who are assessed. "Assessed" is defined as having been referred to the study staff. Enrollment is defined as having been randomized to a treatment arm.

This pilot study will seek to answer whether participants of a clinical trial adhere to a low-dose buprenorphine-naloxone (bup-nx) initiation protocol. The study aims to achieve 80% of study participants meeting adequate fidelity to the low-dose study protocol. Adequate fidelity is defined as meeting all of the following:

• First dose is a low dose (defined as less than 1-.25mg bup-nx) (yes/no),
• Daily bup-nx dose equivalent to assigned daily dose: For the first 7 days the reported total daily bup-nx dose is within the prespecified assigned daily dose limit,
• Variability: Each day's daily dose is increased from the prior daily dose (within daily limits) (yes/no).

Measured using once daily participant self-report through mobile data collection technology.

Uptake is defined as having a positive urine drug test (UDT) for buprenorphine at the 2-week study visit (dichotomous, yes/no).

6-week retention is defined as having an active buprenorphine prescription and buprenorphine-positive UDT at the 6-week visit

The mean number of days of non-prescribed opioid use, defined as self-reported use of heroin, fentanyl, or non-prescribed opioid analgesics in the prior 14 days using an adapted version of the Addiction Severity Index. Will be reported for each arm at the 6-week visit (continuous).

Measured using the Subjective Opioid Withdrawal Score, a 16-item scale based on symptom severity (from 0=Not at all, to 4=extremely). Multilevel mixed-linear effects models will be used to assess between arms.

The percentage of participants who experience precipitated withdrawal during the first 2 weeks of initiation. Defined as withdrawal symptoms that get markedly worse within 90 minutes of taking buprenorphine-naloxone dose. Markedly worse will be defined as a change in 10 points on Subjective Opioid Withdrawal Score (SOWS) severity, or as determined by a study clinician. SOWS is a 16-item scale based on symptom severity (from 0=Not at all, to 4=extremely, yielding a possible overall range from 0-64). Precipitated withdrawal is expected only during periods of increasing buprenorphine-naloxone dose titrations: for the low-dose protocol precipitated withdrawal could occur from dose 1 - 13; for the treatment as usual protocol precipitated withdrawal could occur from dose 1 - 5. SOWS will be collected 5 times/day using daily mobile data collection entries.

The proportion of severe vs mild-moderate buprenorphine-related withdrawal events between study arms will be assessed using the using the Subjective Opioid Withdrawal Score, a 16-item scale based on symptom severity (from 0=Not at all, to 4=extremely). The 16 items are summed with a score of 1-10 representing mild withdrawal, 11-20 as moderate withdrawal, and >/= 21 as severe withdrawal.

Using multilevel mixed-linear effects models to examine effects within individuals (level 1), and between study arms (level 2) of Subjective Opioid Withdrawal Score, 16-items scaled on symptom severity (scale from 0=Not at all to 4=extremely) scored as mild, mod, and severe withdrawal. Data collected using daily mobile data collection technology entries.

Using multilevel mixed-linear effects models to examine effects within individuals (level 1), and between study arms (level 2) of Generalized Anxiety Disorder-7 scale, 7-items scaled on symptom frequency (scale from 0=Not at all to 3=Nearly every day), scored from minimal to severe anxiety. Data collected using daily mobile data collection technology entries.

Using multilevel mixed-linear effects models to examine effects within individuals (level 1), and between study arms (level 2). Measured using two Visual Analog Scale items asking about current cravings and cravings in the past 1-hour, scaled 0-100 on from 0=None at all to 100=Extreme cravings. The score is an average of the results of the two questions. Data collected using daily mobile data collection technology entries.

The mean number of days of non-prescribed opioid use throughout the buprenorphine initiation period. Measured by participant self-report through daily mobile data collection technology entries.

The percent of participants exposed to fentanyl on point of care urine fentanyl test at the 2-week study visit.

The mean number of non-fatal overdose events. Self-reported measure at the 2-week and 6-week study visits.

Proportion of participants of the low-dose initiation arm who meet criteria for strict adherence to the buprenorphine-naloxone (bup-nx) protocol. Defined as having both the correct bup-nx dose (mg) and correct timing each day of the initiation protocol:

• Correct block dose (mg) (yes/no): A reported dose is within the assigned dose limit for specified time block.
• Correct time block (yes/no): A reported dose is within the specified time block for all doses for the first 7 days (doses 1- 13; excluding day 8 doses 14, 15).

Measured using once daily participant self-report through daily mobile data collection technology entries.

Specified time blocks with correct dose and timing / Total number of time blocks in the protocol

Measured as the total time per visit for clinical visits during the study period (continuous). Variable extracted from provider notes in the electronic medical record.

Measured using once daily participant self-report through Ecological Momentary Assessment technology and defined as the proportion of pre-packaged doses taken each day during the initiation protocol.

Proportion of mild vs moderate-severe withdrawal scores at one week. Defined as the Subjective Opioid Withdrawal Score (SOWS) at the 1-week visit. SOWS is a 16-items scaled on symptom severity, with participants reporting whether they have each symptom (0=Not at all to 4=extremely). The 16 items are summed with a score of 1-10 representing mild withdrawal, 11-20 as moderate withdrawal, and >/= 21 as severe withdrawal. SOWS will be collected at a 1-week phone call visit.

Measured using the Obsessive Compulsive Drug Use Scale (OCDUS). The OCDUS an 11 item instrument measuring cravings over 1 week, each item scored on a 5-point Likert scale 0= No craving to 5= Most intense craving, with anchors at each whole interval number, total score calculated by averaging the scores on the 11 items. OCDUS is administered at the 1-week phone call visit.

Measured using the 4-item Patient-Reported Outcomes Measurement (PROMIS) 4a anxiety instrument, each item scaled from 1=Never to 5=Always. The total score is the total additive value of all 4 items, which is then translated into a T-score for each participant using a supplied table. The T-score rescales the raw score into a standardized T-score with a mean of 50 and a standard deviation (SD) of 10. Instrument is administered at the 1-week phone call visit.

The percentage of severe vs mild-moderate buprenorphine-related withdrawal events between study arms will be assessed using the using the Subjective Opioid Withdrawal Score, a 16-item scale based on symptom severity (from 0=Not at all, to 4=extremely). The 16 items are summed with a score of 1-10 representing mild withdrawal, 11-20 as moderate withdrawal, and >/= 21 as severe withdrawal.

Defined as having a positive urine drug test (UDT) for buprenorphine at either a 2-week clinical visit, as per electronic medical record, or research visit (yes/no). Missing either outcome (2-week UDT) will be considered as 'no uptake' (failed initiation).

The dose (mg) of the first bup-nx taken during the initiation process (continuous). Self-reported through mobile data collection technology.

The total bup-nx dose (mg) for each day of the initiation protocol (continuous). Self-reported through mobile data collection technology.

The change in bup-nx dose (mg) between each day of the protocol (continuous). Self-reported through mobile data collection technology.

Self-reported opioid use will be collected daily using mobile data collection technology.